The goal of this research is to synthesize orally active derivatives of a lead compound, neomycin B, that will halt replication of the AIDS virus at the level of transcription by inhibiting the Rev protein/RRE interaction. The association between this protein and sequence of nucleic acid is crucial to the virus life cycle. Recent work has demonstrated that the small molecule antibiotic neomycin B is capable of disrupting the binding of Rev to the RRE. Such an inhibitor would be an effective therapeutic for HIV. However, neomycin B needs improvement in such areas as its cytotoxicity, bioavailability and specificity for the Rev/RRE interaction. Also, syntheses of the large number of compounds necessary to establish SAR would be time consuming and difficult using existing literature methods due to the highly functionalist and saccharide nature of the lead compound. It is proposed to approach this problem by the production of appropriately protected synthons using the commercially available ribostamycin as a starting material. This approach will allow one to produce a large number of neomycin analogs expediently by appending D-ring analogs of wide functional and structural diversity. Once synthesized, multiple assays exist in house to provide activity data on all analogs. PROPOSED COMMERCIAL APPLICATION: An estimated one million people in the U.S. and 17 million worldwide are infected with the AIDS virus. In the U.S., already 243,000 people have died from AIDS. Very few drugs have been approved for treatment of this disease and those that are available have severe limitations including a developing viral resistance. To help overcome this resistance, clinicians are likely to enlist combination therapy as a therapeutic approach. Inhibition of the Rev/RRE interaction with small, orally active molecules will be very appropriate for such combinations because their mode of action is quite distinct from those of reverse transcriptase and protease inhibitors.